Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].C(O)=O>CS(C)=O.O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O=CO
Solvent: O
Product: Cc1ccc(OC(C)(C)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-methyl-3-pyridyloxy)-2-methylpropionate (Step A, 2.0 g, 8.9 mmol) in DMSO (20 mL) was added potassium hydroxide (1.0 g, 20 mmol) in 2 mL water. After stirring at room temperature for 2 h, the reaction was quenched by addition of formic acid (85%, 10 mmol) and poured into water (200 mL). The product was extracted with EtOAc (2×100 mL), and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound contaminated with DMSO (molar ratio 1:5, determined by NMR). 1H NMR (500 MHz, CD3OD): δ 8.06 (d, 1H), 7.38-7.22 (m, 2H), 2.47 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([CH:34]=[O:35])[C:18]4[S:22][C:21]([N:23]5CN(C)C[N:25]([CH2:30][CH3:31])[C:24]5=[O:32])=[N:20][C:19]=4[CH:33]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].OS(O)(=O)=O.[C:46]([O-:49])(O)=O.[Na+].[CH3:51]O>C(Cl)Cl>[CH3:51][O:35][CH:34]([O:49][CH3:46])[C:17]1[C:18]2[S:22][C:21]([NH:23][C:24](=[O:32])[NH:25][CH2:30][CH3:31])=[N:20][C:19]=2[CH:33]=[C:15]([C:12]2[CH:11]=[N:10][C:9]([N:6]3[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:4][CH2:5]3)=[N:14][CH:13]=2)[CH:16]=1
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: O=C([O-])O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(C(OC)OC)c2s1
Temperature: 50 °C

Procedure:
Ethyl 4-ethyl-1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (33 mg, 0.058 mmol) was suspended in MeOH (2 mL) and treated with conc. H2SO4 (˜5 μL). The reaction was heated to 50° C. for 1.5 h then diluted with DCM and sat.NaHCO3(aq). The organic layer was separated and the aqueous layer extracted further with DCM (2×) before the combined DCM extracts were dried and the solvent evaporated to yield the crude product (35 mg). Crude product was used in the next step without further purification. MS: 557.16 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1ccncc1Br
Product: OC(CCCc1ccccc1)c1ccncc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 3-bromo-pyridine-4-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: C(C1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#N.[CH:13](O)=O.[CH2:16]([OH:18])[CH3:17]>[Ni]>[CH:16]([C:17]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:18]
Reactant: CCO
Reactant: Cc1cc(C#N)ccc1C(=O)[O-]
Reactant: O=CO
Agent: [Ni]
Product: COC(=O)c1ccc(C=O)cc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Raney-Ni (3.0 mL, washed with ethanol for 3 times) was added to a solution of 4-cyano-2-methylbenzoate (0.93 g, 5.3 mmol) in ethanol (20 mL). Then formic acid (10 mL, 75%) was added to the mixture. The mixture was stirred at 110° C. for 2 hours. After filtration, the mixture was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to gave product methyl 4-formyl-2-methylbenzoate as a yellow oil (620 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][CH2:11][CH:10]([CH2:13][CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:11][CH:10]([CH2:13][CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)Cl
Reactant: CCC1CNC(c2cccc(Cl)c2)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CN(C(=O)CC(C)C)C(c2cccc(Cl)c2)O1

Procedure:
Four and two-tenths grams of 2-(m-chlorophenyl)-5-ethyl-1,3-oxazolidine was combined with 1.7 g of pyridine in 25 ml of methylene chloride and 2.4 g of isovaleroyl chloride was added dropwise with stirring and the mixture was stirred overnight. The mixture was washed with 50 ml of 5% NaOH and 200 ml of water, dried with MgSO4 and stripped under vacuum. The yield was 2.4 g, nD30 1.5490. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: [H][H]
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccccn2)cc1

Procedure:
4-Aminophenol (27.3 g) in DMF (200 ml) was added dropwise over 30 minutes to a stirred suspension of sodium hydride (10.0 g, 60% dispersion in mineral oil) in DMF (200 ml) with stirring under nitrogen. When the evolution of hydrogen had ceased, 2-bromopyridine (39.5 g) was added and the resultant solution was heated at 120° C. for 6 hours. The DMF was removed under reduced pressure, the residue was dissolved in water (250 ml) and the mixture extracted with dichloromethane. The combined organic extracts were washed with water, 1M sodium hydroxide solution and then again with water and then with 2M hydrochloric acid. The acid extracts were basified and extracted with dichloromethane to give an oil which solidified on standing. This solid was triturated in petroleum ether, b.p. 40°-60° C./ethyl acetate (10:1) to give 4-(2-pyridyloxy)aniline, m.p. 64°-67° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (10 mg, 48%), MS (ISP) m/z=388.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:14][NH2:15])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:16]([O-])([O-])OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][N:11]3[CH:16]=[N:15][N:14]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)n1
Reactant: CCOC([O-])[O-]
Product: Clc1ccc(-c2cnn3cnnc3n2)cc1

Procedure:
A mixture of 4.4 g. of 5-(p-chlorophenyl)-3-hydrazino-1,2,4-triazine and 20 ml. of ethyl orthoformate is refluxed for 4 hours cooled and filtered giving the desired product as light yellow plates, m.p. >300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]([N:30]([CH3:34])[CH2:31][CH2:32][OH:33])([CH3:29])[C:27]#[CH:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:28]#[C:27][C:26]([N:30]([CH3:34])[CH2:31][CH2:32][OH:33])([CH3:29])[CH3:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)N(C)CCO
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Product: CN(CCO)C(C)(C)C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1

Procedure:
In analogy to example 17.3, Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol-5-yl ester and 2-[(1,1-Dimethyl-prop-2-ynyl)-methyl-amino]-ethanol were converted to yield 2-({3-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-1,1-dimethyl-prop-2-ynyl}-methyl-amino)-ethanol as orange viscous oil, MS: 351 (MH+).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][C:13]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][O:14]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:18]([C:13]2([CH3:12])[CH2:17][CH2:16][CH2:15][O:14]2)[OH:19])=[CH:10][CH:11]=1
Reactant: CC1(C=O)CCCO1
Reactant: Cc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(O)C2(C)CCCO2)o1
Temperature: -70 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
24 ml (60 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 5.0 g (60 mmol, 1.5 eq) of 2-methylfuran in 100 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 2 hours. The reaction medium was cooled to −70° C. and then 6.0 g (40 mmol, 1 eq) of 2-methyltetrahydrofuran-2-carbaldehyde at 77% were added. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, filtered over magnesium sulfate and evaporated. 5.21 g of (5-methylfuran-2-yl)-(2-methyltetrahydrofuran-2-yl)methanol were obtained. Yield=66%. TLC/SiO2: heptane/EtOAc (60/40), developing with KMnO4.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C.C(OCC)C>CC(C)=O.CC(CC)=O>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH2:5][CH2:4]1.[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CNC(=O)NCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cl
Temperature: 25 °C

Procedure:
The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl-methyl)-3-(3-phenyl-propyl)-urea (310 mg, 0.79 mmole) was dissolved in acetone (5 ml) and ethyl methyl ketone (15 ml). Chlorotrimethylsilane (150 ml, 1.2 mmole) was added dropwise with stirring at RT. After one hour's stirring, no precipitate had formed. The reaction solution was reduced to approx. 1 ml under a vacuum and combined with diethyl ether (10 ml). The mixture was then vigorously stirred at RT for 1 h. A colorless precipitate was formed. The solid was filtered out, washed with diethyl ether (3×3 ml) and dried under a vacuum. The hydrochloride of the more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-(3-phenyl-propyl)-urea (339 mg, m.p. 85-95° C., 100%; Example 23) was obtained as a colorless solid.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]([NH2:19])=[S:18].[I-:20].[K+].II>CO.C(O)C.O>[IH:20].[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([S:18][C:17](=[NH:16])[NH2:19])=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(N)=S
Reactant: [I-]
Reactant: c1ccc(-n2ccc3ccccc32)cc1
Agent: II
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: I
Product: N=C(N)Sc1cn(-c2ccccc2)c2ccccc12
Yield: 78 %

Procedure:
N-Phenylindole (28.95 g; 0.15M) and thiourea (11.4 g; 0.15M) were dissolved in a mixture of methanol (140 ml) and ethanol (100 ml) by rapid stirring at 20°. To this solution was added in four portions a solution of potassium iodide (52.5 g; 0.3M) and iodine (38.1 g; 0.15M) in water (60 ml) over 10 minutes. The solution was then stirred at 20° for 17 hours. The resulting heavy yellow precipitate of the crude product was filtered off, washed successively with isopropanol (3×200 ml), water (3×200 ml), isopropanol (3×200 ml) and ether (2×200 ml), and then dried at 60° to give the title compound, weight 46.2 g (78.0% yield). An analytical sample was prepared by crystallisation from a 1:1 mixture of methanol and ethanol. This gave colourless rhombohedral crystals of the title compound, m.p. 264°-6°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:11][CH2:12]2)=[N:33][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: NCCc1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCC(C(=NCCc2ccccc2)c2ccc(F)cc2)CC1
Yield: 90.4 %

Procedure:
A mixture of 15.56 g (0.045 mol) of N-benzenesulfonyl-4-(p-fluorobenzoyl)-piperidine, 8.50 g (0.0702 mol) of phenethylamine and 0.20 g (0.0013 mol) of benzenesulfonic acid in 400 mL of toluene was heated at reflux for 111 hr. Water was removed from the reaction mixture with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute Na2CO3. The CH2Cl2 solution was dried (MgSO4), and the solvent was removed in vacuo. The residue was recrystallized from ether to give 18.32 g (90.5%) of title compound as a light tan solid, mp 123°-126° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@@H:12]([NH:16]C(=O)OC(C)(C)C)[CH2:13][O:14][CH3:15])=[CH:6][C:5]=1[NH:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1)(=[O:3])[NH2:2].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[NH2:16][C@@H:12]([CH2:13][O:14][CH3:15])[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:6]=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: COC[C@@H](CNc1ccc(C(N)=O)c(Nc2cc(C)ns2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](N)CNc1ccc(C(N)=O)c(Nc2cc(C)ns2)c1

Procedure:
The above product from step 3 was added TFA in DCM (1:1, 2 mL), 30 min later, the solution was concentrated under vacuum and was purified by preparative HPLC to give (R)-4-(2-amino-3-methoxypropylamino)-2-(3-methylisothiazol-5-ylamino)benzamide as TFA salt. MS 336.2 (M+H); UV 293.8 nm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.C([Sn](CCCC)(CCCC)[C:31]#[C:32][O:33][CH2:34][CH3:35])CCC.[Cl-].C([NH+]([CH2:50][CH3:51])CC)C>CN(C=O)C.O>[CH2:34]([O:33][C:32]#[C:31][C:2]1[CH:3]=[C:4]([O:21][C:22]([F:24])([F:25])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:13])([F:14])[F:15])[C:8]([C:16]([O:18][CH2:50][CH3:51])=[O:17])=[CH:7]2)[CH3:35]
Reactant: CCCC[Sn](C#COCC)(CCCC)CCCC
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Reactant: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (01597/1 PR) (10.6 g, 21.9 mmole), crude tributyl(ethoxyethynyl)stannane prepared as in Step 1 (10.4 g, 28.5 mmole assumed), triethylammonium chloride (3.63 g, 21.9 mmole) and Pd (PPh3)2 (0.769 g, 1.10 mmole) in DMF (140 mL) was stirred at room temperature overnight. The mixture was hen diluted with H2O and extracted with ethyl ether (2×200 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by silica chromatography (5%-6.5% EtOAc:hexanes gradient) gave 4.06 g (44% yield) of the product as a yellow crystalline solid: 1H NMR (dmso-d6/300 MHz) 7.95 (s, 1H), 7.55 (d, 1H, J=2.0 Hz), 7.37 (d, 1H, J=2.2 Hz), 6.11 (q, 1H, J=7.3 Hz), 4.32-4.20 (m, 4H), 1.39 (t, 3H, J=7.1 Hz), 1.26 (t, 3H, J=7.2 Hz).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.[Na]>CN(C=O)C.C(OCC)C>[CH3:6][S:7][C:8]1[NH:9][C:23]([CH3:25])=[C:22]([C:21]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[CH:14]=2)[N:10]=1
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(=O)CC(C)=O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)NC(SC)=NC1c1cccc(OC)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of S-methylisothiourea sulfate (13.9 g), 3-methoxybenzaldehyde (7.5 g), ethyl acetoacetate (6.5 g) and sodium hydrogenocarbonate (21 g) in DMF (200 ml) was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with diethylether and washed with H2O and sat. aq. NaCl. The title compound was purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3OC(=O)[C:17](=[C:21]=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:24][NH2:25].CC[O:28][CH2:29]C>C(O)C>[OH:28][CH2:29][CH:16]1[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:14][CH:13]=2)=[N:25][NH:24][C:21](=[O:22])[CH2:17]1
Reactant: CCOCC
Reactant: NN
Reactant: O=C=C1CC(c2ccc(OCCn3ccnc3)cc2)OC1=O
Solvent: O
Solvent: CCO
Product: O=C1CC(CO)C(c2ccc(OCCn3ccnc3)cc2)=NN1
Reaction time: 16 h

Procedure:
5.2 g (0.017 mol) of 4-(4-(2-(1-imidazolyl)-ethoxy)phenyl)-carbonyl-γ-butyrolactone and 1 ml (0.02 mol) of hydrazine hydrate are stirred in 30 ml of ethanol at room temperature for 1 hour and then at 60° C. for 16 hours. After the mixture has been cooled, 15 ml of ether are added and the precipitated product is filtered off with suction, washed with either and dried.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].CCN(C(C)C)C(C)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(O)CN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Prepare a solution of 1-amino-2-propanol (5.0 g, 66.6 mmol) in methylene chloride (250 mL) at 0° C. under nitrogen. Add Hünig's Base (11.6 mL, 66.6 mmol) followed by benzoyl chloride (7.7 mL, 66.6 mmol). Warm the reaction mixture to room temperature and stir overnight. Wash the solution sequentially with brine (100 mL) and 1M HCl (75 mL), dry (Na2SO4), filter, and concentrate to afford 10.0 g of N-(2-hydroxypropyl)benzamide. MS: m/e=180 (MH+)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:4]([C:9]2[CH:18]=[N:17][C:16]3[C:15](=O)[NH:14][C:13]([CH2:20][O:21][CH3:22])=[N:12][C:11]=3[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[Cl:35][C:15]1[C:16]2[N:17]=[CH:18][C:9]([C:4]3[C:3]([C:2]([F:24])([F:23])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][C:11]=2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2cc(-c3ncccc3C(F)(F)F)cnc2c(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COCc1nc(Cl)c2ncc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Dissolve 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[3,2-d]pyrimidin-4-one (276 mg, 0.822 mmol) in CHCl3 (25 mL) and 2,6-lutidine (294 mg, 2.74 mmol). Add phosphorous oxycloride (0.255 mL, 2.74 mmol) dropwise and heat the resulting solution to reflux for 24 hours. Cool the solution and remove the solvent under reduced pressure. Partition the crude residue between EtOAc (50 mL) and saturated NaHCO3 (aq) (50 mL). Remove the organic phase and extract the aqueous phase with additional EtOAc (50 mL). Combine the two organic extracts, wash with brine (100 mL), and dry over Na2SO4. Remove the solvent to yield the title compound as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[N:20]=[CH:19][S:18][C:14]=2[N:15]=[CH:16][N:17]=1.F[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.[H-].[Na+]>CN(C=O)C.O.Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:21][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[N:20]=[CH:19][S:18][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Cc1cc(O)ccc1OCCNc1ncnc2scnc12
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(C(F)(F)F)ccn2)ccc1OCCNc1ncnc2scnc12
Reaction time: 2 h
Yield: 104 %

Procedure:
3-Methyl-4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethoxy]-phenol (0.13 g, 0.43 mmol) and 2-fluoro-4-trifluoromethylpyridine (0.1 g, 0.6 mmol) were dissolved with magnetic stirring in DMF (4 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. To the solution was added NaH (60% dispersion in oil; 60 mg, 1.5 mmol) and the reaction mixture was stirred for 2 h. The reaction was diluted with H2O (100 mL), and 2 N HCl was added to adjust the pH to 6. After 24 h, a pale brown film had formed on the flask wall. The aqueous supernatant was extracted with Et2O (2×50 mL), and the pooled aqueous fractions were combined with the brown film, and then concentrated in vacuo to yield 0.2 g of a tan semi-solid. Recrystallization from hexane afforded {2-[2-methyl-4-(4-trifluoromethylpyridin-2-yloxy)-phenoxy]-ethyl}-thiazolo[5,4-d]pyrimidin-7-ylamine (Compound 9; 70 mg) as white crystals: mp 107-111° C.; 1H NMR (600 MHz, CDCl3) δ 8.78 (s, 1H), 8.53 (s, 1H), 8.29 (d, J=5.2 Hz, 1H), 7.17-7.11 (m, 1H), 7.08 (s, 1H), 6.92-6.90 (m, 2H), 6.85 (d, J=8.7 Hz, 1H), 6.56 (s, 1H), 4.29-4.20 (m, 2H), 4.11 (d, J=4.4 Hz, 2H), 2.25 (s, 3H); ESIMS m/z 448.1 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23])[CH3:11]>>[CH2:10]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[S:23][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)[CH3:11]
Reactant: NC1(CCl)CCCC1
Reactant: CCc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Product: CCc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.